Chloride Ion Transport by PITENINs across the Phospholipid Bilayers of Vesicles and Cells

Small-molecule-based Cl^- ion carriers are gaining revived attention because of their recently discovered role toward anticancer activity. Herein, we showed that the anticancer agents, PITENINs, have an efficient transmembrane Cl^- ion transport activity. Theoretical calculations, ¹H NMR titration, and spectrophotometric analysis suggest that the PITENINs strongly bind with a Cl^- ion. In addition to the lipophilicity, the presence of both acylthiourea and phenolic OH moieties of the compounds plays a crucial role in the transport of Cl^- ions. Among the tested compounds, PIT-1 and DM-PIT-1 showed higher Cl^- ion selectivity and transport efficiency. Mechanistic studies demonstrated that the potent compounds follow the H⁺/Cl^- transport pathway. Cellular activity studies showed that the disruption of Cl^- ion homeostasis by PIT-1 and DM-PIT-1 preferentially promotes apoptotic cell death.